This invention relates to certain piperidine quaternary salts that are CCR-3 receptor antagonists, pharmaceutical compositions containing them, methods for their use and methods for preparing these compounds.
Tissue eosinophilia is a feature of a number of pathological conditions such as asthma, rhinitis, eczema and parasitic infections ((see Bousquet, J. et al. N. Eng. J. Med. 323: 1033-1039 (1990) and Kay, A. B. and Corrigan. C. J. Br. Med. Bull. 48:51-64 (1992)). In asthma, eosinophil accumulation and activation are associated with damage to bronchial epithelium and hyperresponsiveness to constrictor mediators. Chemokines such as RANTES, eotaxin and MCP-3 are known to activate eosinophils ((see Baggiolini, M. and Dahinden, C. A. Immunol. Today. 15:127-133 (1994), Rot, A. M. et al. J. Exp. Med. 176, 1489-1495 (1992) and Ponath. P. D. et al. J. Clin. Invest., Vol. 97, #3, 604-612 (1996)). However, unlike RANTES and MCP-3 which also induce the migration of other leukocyte cell types, eotaxin is selectively chemotactic for eosinophils ((see Griffith-Johnson, D. A et al. Biochem. Biophy. Res. Commun. 197:1167 (1993) and Jose, P. J. et al. Biochem. Biophy. Res. Commun. 207, 788 (1994)). Specific eosinophil accumulation was observed at the site of administration of eotaxin whether by intradennal or intraperitoneal injection or aerosol inhalation ((see Griffith-Johnson, D. A et al. Biochem. Biophy. Res. Commun. 197:1167 (1993); Jose, P. J. et al. J. Exp. Med. 179, 881-887 (1994); Rothenberg, M. E. et al. J. Exp. Med. 181, 1211 (1995) and Ponath. P. D. J. Clin. Invest., Vol. 97, #3, 604-612 (1996)).
Glucocorticoids such as dexamethasone, methprednisolone and hydrocortisone have been used for treating many eosinophil-related disorders, including bronchial asthma ((R. P. Schleimer et. al., Am. Rev. Respir. Dis., 141, 559 (1990)). The glucocorticoids are believed to inhibit IL-5, IL3 mediated eosinophil survival in these diseases. However, prolonged use of glucocorticoids can lead to side effects such as glaucoma, osteoporosis and growth retardation in the patients ((see Hanania N. A et al., J. Allergy and Clin. Immunol., Vol. 96, 571-579 (1995) and Saha M. T. et al, Acta Paediatrica, Vol. 86, #2, 138-142 (1997)). It is therefore desirable to have an alternative means of treating eosinophil related diseases without incurring these undesirable side effects.
Recently, the CCR-3 receptor was identified as a major chemokine receptor that eosinophils use for their response to eotaxin, RANTES and MCP-3. When transfected into a murine pre-xcex2 lymphoma line, CCR-3 bound eotaxin, RANTES and MCP-3 and conferred chemotactic responses on these cells to eotaxin, RANTES and MCP-3 ((see Ponath. P. D. et al. J. Exp. Med. 183, 2437-2448 (1996)). The CCR-3 receptor is expressed on the surface of eosinophils, T-cells (subtype Th-2), basophils and mast cells and is highly selective for eotaxin.
Studies have shown that pretreatment of eosinophils with an anti-CCR-3 mAb completely inhibits eosinophil chemotaxis to eotaxin, RANTES and MCP-3 ((see Heath H. et al. J. Clin. Invest., Vol. 99, #2, 178-184 (1997)). Applicants"" U.S. patent application Ser. No. 09/134,013, filed Aug. 14, 1998 discloses compounds that are CCR-3 antagonists and inhibit eosinophilic recruitment by chemokines such as eotaxin. PCT Application WO 98/04554 discloses piperidine analogs that are CCR-3 receptor antagonists.
Therefore, blocking the ability of the CCR-3 receptor to bind RANTES, MCP-3 and eotaxin and thereby preventing the recruitment of eosinophils should provide for the treatment of eosinophil-mediated inflammatory diseases.
The present invention concerns novel piperidine quaternary salts which are capable of inhibiting the binding of eotaxin to the CCR-3 receptor and thereby provide a means of combating eosinophil induced diseases, such as asthma.
In a first aspect, this invention provides compounds selected from the group of compounds represented by Formula (I): 
wherein:
One of T and U is xe2x80x94N+R5xe2x80x94 where R5 is alkyl, haloalkyl, cyanoalkyl, hydroxyalkyl, alkoxyalkyl, carboxyalkyl, alkoxycarbonylalkyl, amidoalkyl, sulfonylaminoalkyl, or aralkyl and the other is xe2x80x94CHxe2x80x94;
Xxe2x88x92 is a pharmaceutically acceptable counterion;
R1 and R2 are, independently of each other, hydrogen or alkyl;
m is an integer from 0 to 3 provided that when T is xe2x80x94N+R5xe2x80x94 then m is at least 1;
Ar and Ar1 are, independently of each other, aryl or heteroaryl;
F is alkylene, alkenylene, or a bond;
R is hydrogen or alkyl; or R together with either R3 or R4 and the atoms to which they are attached forms a carbocycle or a heterocycle;
R3 and R4 are, independently of each other, hydrogen, alkyl, alkenyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, heterocyclyl, heterocyclylalkyl, heteroalkyl, or -(alkylene)-C(O)xe2x80x94Z where Z is alkyl, haloalkyl, alkoxy, haloalkyloxy, hydroxy, amino, mono- or disubstituted amino, aryl, aralkyl, aryloxy, aralkyloxy, heteroaryl, heteroaryloxy, or heteroaralkyloxy;
E is xe2x80x94C(O)N(R6)xe2x80x94, xe2x80x94SO2N(R6)xe2x80x94, xe2x80x94N(R7)C(O)N(R6)xe2x80x94, xe2x80x94N(R7)SO2N(R6)xe2x80x94, xe2x80x94N(R7)C(S)N(R6)xe2x80x94, xe2x80x94N(R7)C(O)xe2x80x94 or xe2x80x94N(R7)SO2xe2x80x94 where:
R6 and R7 are, independently of each other, hydrogen, alkyl, acyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heterocycloalkyl, heteroalkyl, or -(alkylene)-C(O)xe2x80x94Z where Z is alkyl, haloalkyl, alkoxy, haloalkyloxy, hydroxy, amino, mono- or disubstituted amino, aryl, aralkyl, aryloxy, aralkyloxy, heteroaryl, heteroaryloxy, or heteroaralkyloxy;
Q is xe2x80x94COxe2x80x94 or an alkylene chain optionally interrupted by xe2x80x94C(O)xe2x80x94, xe2x80x94NR8xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94S(O)0xe2x88x922xe2x80x94, xe2x80x94C(O)N(R8)xe2x80x94, xe2x80x94N(R8)C(O)xe2x80x94, xe2x80x94N(R8)SO2xe2x80x94, xe2x80x94SO2N(R8)xe2x80x94, xe2x80x94N(R9)C(O)N(R10)xe2x80x94, xe2x80x94N(R9)SO2N(R10)xe2x80x94 or xe2x80x94N(R9)C(S)N(R10)xe2x80x94 where:
R8, R9 and R10 are, independently of each other, hydrogen, alkyl, acyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, aralkenyl, heteroaryl, heteroaralkyl, heterocyclylalkyl, heteroalkyl, or -(alkylene)-C(O)xe2x80x94Z where Z is alkyl, haloalkyl, alkoxy, haloalkyloxy, hydroxy, amino, mono- or disubstituted amino, aryl, aralkyl, aryloxy, aralkyloxy, heteroaryl, heteroaryloxy, or heteroaralkyloxy; and
prodrugs, individual isomers, mixtures of isomers, and pharmaceutically acceptable salts thereof.
In a second aspect, this invention provides pharmaceutical compositions containing a therapeutically effective amount of a compound of Formula (I) or its pharmaceutically acceptable salt and a pharmaceutically acceptable excipient.
In a third aspect, this invention provides a method of treatment of a disease in a mammal treatable by administration of a CCR-3 receptor antagonist, comprising administration of a therapeutically effective amount of a compound of Formula (I) or its pharmaceutically acceptable salt. The disease states include respiratory diseases such as asthma.
In a fourth aspect, this invention provide a process for preparing compounds of Formula (I).
Unless otherwise stated, the following terms used in the specification and claims have the meanings given below:
xe2x80x9cAlkylxe2x80x9d means a linear saturated monovalent hydrocarbon radical of one to six carbon atoms or a branched saturated monovalent hydrocarbon radical of three to six carbon atoms, e.g., methyl, ethyl, propyl, 2-propyl, pentyl, and the like.
xe2x80x9cAlkenylxe2x80x9d means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three to six carbon atoms, containing at least one double bond, e.g., ethenyl, propenyl, and the like.
xe2x80x9cAlkylenexe2x80x9d means a linear saturated divalent hydrocarbon radical of one to six carbon atoms or a branched saturated divalent hydrocarbon radical of three to six carbon atoms, e.g., methylene, ethylene, propylene, 2-methylpropylene, pentylene, and the like.
xe2x80x9cAlkenylenexe2x80x9d means a linear divalent hydrocarbon radical of two to six carbon atoms or a branched divalent hydrocarbon radical of three to six carbon atoms, containing at least one double bond, e.g., ethenylene, 2,4-pentadienylene, and the like.
xe2x80x9cAcylxe2x80x9d means a radical xe2x80x94C(O)R where R is alkyl, alkenyl, cycloalkyl, heteroalkyl, haloalkyl, aryl, aralkyl, heteroaralkyl or heteroaryl, e.g., acetyl, benzoyl, thenoyl, and the like.
xe2x80x9cAcyloxyxe2x80x9d means a radical xe2x80x94OC(O)R where R is hydrogen, alkyl, cycloalkyl, heteroalkyl, haloalkyl or optionally substituted phenyl, e.g., acetoxy, benzoyloxy, and the like.
xe2x80x9cAcylarninoxe2x80x9d means a radical xe2x80x94NRC(O)Rxe2x80x2 where R is hydrogen or alkyl and Rxe2x80x2 is alkyl, cycloalkyl, heteroalkyl, haloalkyl or optionally substituted phenyl, e.g., acetylamino, trifluoroacetylamino, benzoylamino, methylacetylamino, and the like.
xe2x80x9cHaloxe2x80x9d means fluoro, chloro, bromo or iodo, preferably fluoro and chloro.
xe2x80x9cHaloalkylxe2x80x9d means alkyl substituted with one or more same or different halo atoms, e.g., xe2x80x94CH2Cl, xe2x80x94CF3, xe2x80x94CH2CF3, xe2x80x94CH2CCl3, and the like.
xe2x80x9cCycloalkylxe2x80x9d means a saturated monovalent cyclic hydrocarbon radical of three to six ring carbons, e.g., cyclopropyl, cyclohexyl, and the like.
xe2x80x9cCarbocyclexe2x80x9d means a saturated, cyclic group of 3 to 6 ring atoms in which all the ring atoms are carbon, e.g., cyclopentyl, cyclohexyl, and the like.
xe2x80x9cMonosubstituted-aminoxe2x80x9d means a radical xe2x80x94NHR where R is alkyl, heteroalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl or optionally substituted phenyl, e.g., methylamino, (1-methylethyl)amino, phenylamino, and the like.
xe2x80x9cDisubstituted-aminoxe2x80x9d means a radical xe2x80x94NRRxe2x80x2 where R and Rxe2x80x2 are independently alkyl, alkenyl, heteroalkyl, haloalkyl, cycloalkyl, cycloalkylalkyl or optionally substituted phenyl. Representative examples include, but are not limited to, dimethylamino, methylethylamino, di(1-methylethyl)amino, and the like.
xe2x80x9cArylxe2x80x9d means a monovalent monocyclic or bicyclic aromatic hydrocarbon radical of 6 to 10 ring atoms, and optionally substituted independently with one or more substituents, preferably one, two or three substituents selected from alkyl, haloalkyl, heteroalkyl, cycloalkyl, cycloalkylalkyl, halo, cyano, nitro, acyloxy, alkoxy, optionally substituted phenyl, heteroaryl, heteroaralkyl, amino, monosubstituted amino, disubstituted amino, acylamino, hydroxylarnino, amidino, guanidino, cyanoguanidinyl, hydrazino, hydrazido, xe2x80x94OR [where R is hydrogen, haloalkyl, alkenyl, cycloalkyl, cycloalkylalkyl, optionally substituted phenyl, heteroaryl or heteroaralkyl], xe2x80x94S(O)nR [where n is an integer from 0 to 2 and R is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, optionally substituted phenyl, heteroaryl, heteroaralkyl, amino, mono- or disubstituted amino], xe2x80x94NRSO2Rxe2x80x2 (where R is hydrogen or alkyl and Rxe2x80x2 is alkyl, amino, mono- or disubstituted amino), xe2x80x94C(O)R (where R is hydrogen, alkyl, cycloalkyl, heteroalkyl, haloalkyl or optionally substituted phenyl), xe2x80x94COOR (where R is hydrogen, alkyl, optionally substituted phenyl, heteroaryl or heteroaralkyl), -(alkylene)COOR (where R is hydrogen, alkyl, optionally substituted phenyl, heteroaryl or heteroaralkyl), methylenedioxy, 1,2-ethylenedioxy, xe2x80x94CONRxe2x80x2Rxe2x80x3 or -(alkylene)CONRxe2x80x2Rxe2x80x3 (where Rxe2x80x2 and Rxe2x80x3 are independently selected from hydrogen, alkyl, cycloalkyl, haloalkyl, cycloalkylalkyl, optionally substituted phenyl, heteroaryl and heteroaralkyl). More specifically the term aryl includes, but is not limited to, phenyl, 1-naphthyl, 2-naphthyl, and derivatives thereof.
xe2x80x9cOptionally substituted phenylxe2x80x9d means a phenyl group which is optionally substituted independently with one, two or three substituents selected from alkyl, haloalkyl, halo, nitro, cyano, xe2x80x94OR (where R is hydrogen or alkyl), xe2x80x94NRRxe2x80x2 (where R and Rxe2x80x2 are independently of each other hydrogen or alkyl), xe2x80x94COOR (where R is hydrogen or alkyl) or xe2x80x94CONRxe2x80x2Rxe2x80x3 (where Rxe2x80x2 and Rxe2x80x3 are independently selected from hydrogen or alkyl).
xe2x80x9cHeteroarylxe2x80x9d means a monovalent monocyclic or bicyclic aromatic radical of 5 to 10 ring atoms containing one, two, or three ring heteroatoms selected from N, O, or S, the remaining ring atoms being C. The aromatic radical is optionally substituted independently with one or more substituents, preferably one or two substituents selected from alkyl, haloalkyl, heteroalkyl, cycloalkyl, cycloalkylalkyl, halo, cyano, nitro, acyloxy, optionally substituted phenyl, amino, mono- or disubstituted amino, acylamino, hydroxyamino, amidino, guanidino, cyanoguanidinyl, hydrazino, hydrazido, xe2x80x94OR [where R is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl or optionally substituted phenyl], xe2x80x94S(O),R [where n is an integer from 0 to 2 and R is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, optionally substituted phenyl, amino, mono- or disubstituted amino], xe2x80x94C(O)R (where R is hydrogen, alkyl, cycloalkyl, heteroalkyl, haloalkyl or optionally substituted phenyl), xe2x80x94COOR (where R is hydrogen, alkyl, or optionally substituted phenyl), -(alkylene)COOR (where R is hydrogen, alkyl or optionally substituted phenyl), methylenedioxy, 1,2-ethylenedioxy, xe2x80x94CONRxe2x80x2Rxe2x80x3 or -(alkylene)xe2x80x94CONRxe2x80x2Rxe2x80x3 (where Rxe2x80x2 and Rxe2x80x3 are independently selected from hydrogen, alkyl, cycloalkyl, haloalkyl, cycloalkylalkyl or optionally substituted phenyl). More specifically the term heteroaryl includes, but is not limited to, pyridyl, pyrrolyl, thiophene, pyrazolyl, thiazolyl, imidazolyl, pyrimidinyl, thiadiazolyl, indolyl, carbazolyl, azaindolyl, benzofuranyl, benzotriazolyl, benzisoxazolyl, purinyl, quinolinyl, benzopyranyl, and derivatives thereof.
xe2x80x9cHeterocyclexe2x80x9d or xe2x80x9cHeterocyclylxe2x80x9d means a saturated or unsaturated cyclic radical of 3 to 8 ring atoms in which one or two ring atoms are heteroatoms selected from N, O, or S(O)n (where n is an integer from 0 to 2). The heterocyclo ring may be optionally substituted independently with one, two or three substituents selected from alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, aryl, aralkyl, heteroaryl, heteroaralkyl, halo, cyano, acyl, acylamino, amino, monosubstituted amino, disubstituted amino, xe2x80x94COOR (where R is hydrogen or alkyl), xe2x80x94XR (where X is O or S(O)., where n is an integer from 0 to 2 and R is hydrogen, alkyl, haloalkyl, cycloalkyl, aralkyl, aryl, heteroaryl or heteroaralkyl) or xe2x80x94CONRxe2x80x2Rxe2x80x3 (where Rxe2x80x2 and Rxe2x80x3 are independently selected from hydrogen or alkyl). Representative examples include, but are not limited to tetrahydropyranyl, piperidino, 1-(4-chlorophenyl)piperidino, and the like.
xe2x80x9cHeteroalkylxe2x80x9d means an alkyl, cycloalkyl, or cycloalkylalkyl radical as defined above, carrying a substituent containing a heteroatom selected from N, O, S(O)n where n is an integer from 0 to 2. Representative substituents include xe2x80x94NRaRb, xe2x80x94ORa or xe2x80x94S(O)nRc, wherein n is an integer from 0 to 2, Ra is hydrogen, alkyl, haloalkyl, cycloalkyl, cycloalkylalkyl, optionally substituted phenyl, pyridyl, xe2x80x94COR (where R is alkyl or alkoxy) or aminoalkyl, Rb is hydrogen, alkyl, xe2x80x94SO2R (where R is alkyl or hydroxyalkyl), xe2x80x94SO2NRRxe2x80x2 (where R and Rxe2x80x2 are independently of each other hydrogen or alkyl), xe2x80x94CONRxe2x80x2Rxe2x80x3, (where Rxe2x80x2 and Rxe2x80x3 are independently selected from hydrogen or alkyl) and Rc is hydrogen, alkyl, cycloalkyl, cycloalkylalkyl, optionally substituted phenyl, amino, mono- or disubstituted amino. Representative examples include, but are not limited to 2-methoxyethyl, benzyloxymethyl, and the like.
xe2x80x9cHydroxyalkylxe2x80x9d means a linear monovalent hydrocarbon radical of two to six carbon atoms or a branched monovalent hydrocarbon radical of three or six carbons substituted with one or two hydroxy groups, provided that if two hydroxy groups are present they are not both on the same carbon atom. Representative examples include, but are not limited to, 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 1-(hydroxymethyl)-2-methylpropyl, 2-hydroxybutyl, 3-hydroxybutyl, 4-hydroxybutyl, 2,3-dihydroxypropyl, 1-(hydroxymethyl)-2-hydroxyethyl, 2,3-dihydroxybutyl, 3,4-dihydroxybutyl and 2-(hydroxymethyl)-3-hydroxypropyl, preferably 2-hydroxyethyl, 2,3-dihydroxypropyl, and 1-(hydroxymethyl)-2-hydroxyethyl, preferably 2-hydroxyethyl, 2-hydroxypropyl, 3-hydroxypropyl, 2,3-dihydroxypropyl, and 4-hydroxybutyl.
xe2x80x9cAminoalkylxe2x80x9d means an alkyl radical as defined above, carrying one or two amino groups, e,g., 2-arninoethyl, 2-aminopropyl, 3-aminopropyl, 1-(aminomethyl)-2-methylpropyl, and the like.
xe2x80x9cAmidoalkylxe2x80x9d means an alkyl radical as defined above, carrying a xe2x80x94NRCORa group where R is hydrogen or alkyl and Ra is alkyl as defined above, e,g., xe2x80x94(CH2)2NHCOCH3, xe2x80x94(CH2)3NHCOCH3, and the like.
xe2x80x9cSulfonylaminoalkylxe2x80x9d means an alkyl radical as defined above, carrying a xe2x80x94NRSO2Ra group, e,g., xe2x80x94(CH2)2NHSO2CH3, xe2x80x94(CH2)3NHSO2CH3, xe2x80x94(CH2)2NHSO2C2H5, and the like.
xe2x80x9cCarboxyalkylxe2x80x9d means an alkyl radical as defined above, carrying a carboxy group, e,g., carboxymethyl, 2-carboxyethyl, 2-carboxypropyl, 3-carboxypropyl, 1-(carboxymethyl)-2-methyl-propyl, and the like.
xe2x80x9cAlkoxycarbonylalkylxe2x80x9d means an alkyl radical as defined above, carrying a xe2x80x94COOR group where R is an alkyl group as defined above, e,g., 2-methoxycarbonylethyl, ethoxycarbonylmethyl, 2-ethoxycarbonylethyl, 3-ethoxycarbonylpropyl, 3-methoxycarbonylpropyl, and the like.
xe2x80x9cAlkoxyalkylxe2x80x9d means an alkyl radical as defined above, carrying an alkoxy group, e,g., methoxymethyl, 2-methoxyethyl, 2-methoxypropyl, 3-methoxypropyl, 1-(methoxymethyl)-2-methylpropyl, and the like.
xe2x80x9cCyanoalkylxe2x80x9d means an alkyl radical as defined above, carrying a cyano group, e,g., 2-cyanoethyl, 2-cyanopropyl, 3-cyanopropyl, 1-(cyanomethyl)-2-methylpropyl, and the like.
xe2x80x9cCycloalkylalkylxe2x80x9d means a radical -R Rb where Ra is an alkylene group and Rb is a cycloalkyl group as defined above e.g., cyclopropylmethyl, cyclohexylpropyl, 3-cyclohexyl-2-methylpropyl, and the like.
xe2x80x9cAralkylxe2x80x9d means a radical xe2x80x94Ra Rb where Ra is an alkylene group and Rb is an aryl group as defined above e.g., benzyl, phenylethyl, 3-(3-chlorophenyl)-2-methylpentyl, and the like.
xe2x80x9cHeteroaralkylxe2x80x9d means a radical xe2x80x94Ra Rb where Ra is an alkylene group and Rb is a heteroaryl group as defined above e.g., pyridin-3-ylmethyl, 3-(benzofuran-2-yl)propyl, and the like.
xe2x80x9cHeterocyclylalkylxe2x80x9d means a radical xe2x80x94Ra Rb where Ra is an alkylene group and Rb is a heterocyclyl group as defined above e.g., tetrahydropyran-2-ylmethyl, 4-methylpiperazin-1-ylethyl, and the like.
xe2x80x9cAlkoxyxe2x80x9d, xe2x80x9chaloalkyloxyxe2x80x9d, xe2x80x9caryloxyxe2x80x9d, xe2x80x9cheteroaryloxyxe2x80x9d, xe2x80x9caralkyloxyxe2x80x9d, or xe2x80x9cheteroaralkyloxyxe2x80x9d means a radical xe2x80x94OR where R is an alkyl, haloalkyl, aryl, heteroaryl, aralkyl, or heteroaralkyl respectively as defined above e.g., methoxy, phenoxy, pyridin-2-yloxy, benzyloxy, and the like.
xe2x80x9cOptionalxe2x80x9d or xe2x80x9coptionallyxe2x80x9d means that the subsequently described event or circumstance may but need not occur, and that the description includes instances where the event or circumstance occurs and instances in which it does not. For example, xe2x80x9cheterocyclo group optionally mono- or di-substituted with an alkyl groupxe2x80x9d means that the alkyl may but need not be present, and the description includes situations where the heterocyclo group is mono- or disubstituted with an alkyl group and situations where the heterocyclo group is not substituted with the alkyl group.
xe2x80x9cAmino-protecting groupxe2x80x9d refers to those organic groups intended to protect nitrogen atoms against undesirable reactions during synthetic procedures e.g., benzyl benzyloxycarbonyl (CBZ), t-butoxycarbonyl (BOC), trifluoroacetyl, and the like.
Compounds that have the same molecular formula but differ in the nature or sequence of bonding of their atoms or the arrangement of their atoms in space are termed xe2x80x9cisomersxe2x80x9d. Isomers that differ in the arrangement of their atoms in space are termed xe2x80x9cstereoisomersxe2x80x9d. Stereoisomers that are not mirror images of one another are termed xe2x80x9cdiastereomersxe2x80x9d and those that are non-superimposable mirror images of each other are termed xe2x80x9cenantiomersxe2x80x9d. When a compound has an asymmetric center, for example, where a carbon atom is bonded to four different groups, a pair of enantiomers is possible. An enantiomer can be characterized by the absolute configuration of its asymmetric center and is described by the R- and S-sequencing rules of Cahn and Prelog, or by the manner in which the molecule rotates the plane of polarized light and designated as dextrorotatory or levorotatory (i.e., as (+) or (xe2x88x92)-isomers respectively). A chiral compound can exist as either individual enantiomer or as a mixture thereof. A mixture containing equal proportions of the enantiomers is called a xe2x80x9cracemic mixturexe2x80x9d.
The compounds of this invention may possess one or more asymmetric centers; such compounds can therefore be produced as individual (R)- or (S)-stereoisomers or as mixtures thereof. For example, if the R3 and R4 substituents in a compound of Formula (I) are different, then the carbon to which they are attached is an asymmetric center and the compound of Formula (I) can exist as an (R)- or (S)-stereoisomer. Unless indicated otherwise, the description or naming of a particular compound in the specification and claims is intended to include both individual enantiomers and mixtures, racemic or otherwise, thereof. The methods for the determination of stereochemistry and the separation of stereoisomers are well-known in the art (see discussion in Chapter 4 of xe2x80x9cAdvanced Organic Chemistryxe2x80x9d, 4th edition J. March, John Wiley and Sons, New York, 1992).
A xe2x80x9cpharmaceutically acceptable excipientxe2x80x9d means an excipient that is useful in preparing a pharmaceutical composition that is generally safe, non-toxic and neither biologically nor otherwise undesirable, and includes an excipient that is acceptable for veterinary use as well as human pharmaceutical use. xe2x80x9cA pharmaceutically acceptable excipientxe2x80x9d as used in the specification and claims includes both one and more than one such excipient.
A xe2x80x9cpharmaceutically acceptable counterionxe2x80x9d means an ion having a charge opposite to that of the substance with which it is associated and that is pharmaceutically acceptable. Representative examples include, but are not limited to, chloride, bromide, iodide, methanesulfonate, p-tolylsulfonate, trifluoroacetate, acetate, and the like.
A xe2x80x9cpharmaceutically acceptable saltxe2x80x9d of a compound means a salt that is pharmaceutically acceptable and that possesses the desired pharmacological activity of the parent compound. Such salts include:
(1) acid addition salts, formed with inorganic acids such as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, phosphoric acid, and the like; or formed with organic acids such as acetic acid, propionic acid, hexanoic acid, cyclopentanepropionic acid, glycolic acid, pyruvic acid, lactic acid, malonic acid, succinic acid, malic acid, maleic acid, fumaric acid, tartaric acid, citric acid, benzoic acid, 3-(4-hydroxybenzoyl)-benzoic acid, cinnamic acid, mandelic acid, methanesulfonic acid, ethanesulfonic acid, 1,2-ethane-disulfonic acid, 2-hydroxyethanesulfonic acid, benzenesulfonic acid, 4-chlorobenzenesulfonic acid, 2-napthalenesulfonic acid, 4-toluenesulfonic acid, camphorsulfonic acid, 4-methylbicyclo[2.2.2]oct-2-ene-1-carboxylic acid, glucoheptonic acid, 4,4-methylenebis-(3-hydroxy-2-ene-1-carboxylic acid), 3-phenylpropionic acid, trimethylacetic acid, tertiary butylacetic acid, lauryl sulfuric acid, gluconic acid, glutamic acid, hydroxynapthoic acid, salicylic acid, stearic acid, muconic acid, and the like; or
(2) salts formed when an acidic proton present in the parent compound either is replaced by a metal ion, e.g., an alkali metal ion, an alkaline earth ion, or an aluminum ion; or coordinates with an organic base such as ethanolamine, diethanolamine, triethanolamine, tromethamine, N-methylglucamine, and the like.
xe2x80x9cLeaving groupxe2x80x9d has the meaning conventionally associated with it in synthetic organic chemistry i.e., an atom or group capable of being displaced by a nucleophile and includes halogen, alkanesulfonyloxy, arenesulfonyloxy, ester, or amino such as chloro, bromo, iodo, mesyloxy, tosyloxy, trifluorosulfonyloxy, methoxy, N,O-dimethylhydroxyl-amino, and the like.
xe2x80x9cPro-drugsxe2x80x9d means any compound which releases an active parent drug according to Formula (I) in vivo when such prodrug is administered to a mammalian subject. Prodrugs of a compound of Formula (I) are prepared by modifying functional groups present in the compound of Formula (I) in such a way that the modifications may be cleaved in vivo to release the parent compound. Prodrugs include compounds of Formula (I) wherein a hydroxy, sulfhydryl or amino group in compound (I) is bonded to any group that may be cleaved in vivo to regenerate the free hydroxyl, amino, or sulfhydryl group, respectively. Examples of prodrugs include, but are not limited to esters (e.g., acetate, formate, and benzoate derivatives), carbamates (e.g., N,N-dimethylaminocarbonyl) of hydroxy functional groups in compounds of Formula (I), and the like.
xe2x80x9cTreatingxe2x80x9d or xe2x80x9ctreatmentxe2x80x9d of a disease includes:
(1) preventing the disease, i.e. causing the clinical symptoms of the disease not to develop in a mammal that may be exposed to or predisposed to the disease but does not yet experience or display symptoms of the disease,
(2) inhibiting the disease, i.e., arresting or reducing the development of the disease or its clinical symptoms, or
(3) relieving the disease, i.e., causing regression of the disease or its clinical symptoms.
A xe2x80x9ctherapeutically effective amountxe2x80x9d means the amount of a compound that, when administered to a mammal for treating a disease, is sufficient to effect such treatment for the disease. The xe2x80x9ctherapeutically effective amountxe2x80x9d will vary depending on the compound, the disease and its severity and the age, weight, etc., of the mammal to be treated.
The nomenclature used in this application is generally based on the IUPAC recommendations, e.g.,
a compound of Formula (I) where T is xe2x80x94N+R5xe2x80x94, U is carbon, m is 1, R, R1, R2 and R3 are hydrogen, R4 is 1-methylethyl, R5 is ethyl, X is iodide, E is xe2x80x94NHC(O)NHxe2x80x94, F is a bond, Q is xe2x80x94CH2xe2x80x94, Ar is 3,4,5-trimethoxyphenyl, Ar1 is 3,4-chlorophenyl and the stereochemistry at the carbon to which R3 and R4 are attached is R is named, 4-(3,4-dichlorobenzyl)-1-ethyl-1-{3-methyl-2(R)-[3-(3,4,5-trimethoxyphenyl)ureido]butyl}-piperidinium iodide.
a compound of Formula (I) where T is xe2x80x94N+R5xe2x80x94, U is carbon, m is 1, R, R1, R2 and R3 are hydrogen, R4 is 1-methylethyl, R is methyl, X is chloride, E is xe2x80x94C(O)NHxe2x80x94, F is a bond, Q is xe2x80x94CH2xe2x80x94, Ar is 4-(2-aminoethyl)phenyl, Ar1 is 3,4-chlorophenyl and the stereochemistry at the carbon to which R3 and R4 are attached is R is named, 1-{2-(R)-[4-(2-arninoethyl)-benzoylamino]-3-methylbutyl}-4-(3,4-dichlorobenzyl)-1-methyl-piperidinium chloride.
Representative compounds of this invention are as follows:
I. Representative compounds of Formula (I) where T=xe2x80x94N+R5xe2x80x94; U=carbon; m=1; R=R1=R2=R3=hydrogen; Fxe2x95x90bond; Qxe2x95x90xe2x80x94CH2xe2x80x94; E=xe2x80x94C(O)NHxe2x80x94 and other groups are as defined below are:
II. Representative compounds of Formula (I) where T=carbon; U=xe2x80x94N+R5xe2x80x94; m=0; R=R1=R2=R3=hydrogen; Fxe2x95x90bond; Qxe2x95x90xe2x80x94CH2xe2x80x94; E=xe2x80x94C(O)NHxe2x80x94 and other groups are as defined below are:
III. Representative compounds of Formula (I) where T=xe2x80x94N+R5xe2x80x94; U=carbon; m=1; R=R1=R2=R3=hydrogen; Fxe2x95x90bond; Qxe2x95x90xe2x80x94CH2xe2x80x94; E=xe2x80x94NHC(O)NHxe2x80x94 and other groups are as defined below are:
While the broadest definition of this invention is set forth in the Summary of the Invention, certain compounds of Formula (I) are preferred.
(I) A preferred group of compounds is that wherein:
T is xe2x80x94N+R5xe2x80x94 wherein R5 is alkyl, hydroxyalkyl, alkoxycarbonylalkyl, preferably methyl, ethyl, 2-hydroxyethyl, 3-hydroxypropyl, methoxycarbonylmethyl, ethoxycarbonylmethyl, most preferably methyl, ethyl, or 2-hydroxyethyl;
m is 1;
R, R1, R2 and R3 are hydrogen;
F is a bond;
Q is an alkylene chain, more preferably methylene or ethylene, most preferably methylene.
(A) Within this group (I), a more preferred group of compounds is that wherein:
E is xe2x80x94C(O)NHxe2x80x94; and
R4 is alkyl or heteroalkyl, preferably 1-methylethyl, 1,1-dimethylethyl, 2-methylpropyl, 3-hydroxypropyl, 1-hydroxyethyl or 2-hydroxyethyl, more preferably 1-methylethyl or 1,1-dimethylethyl.
Within the preferred and more preferred groups, an even more preferred group of compounds is that wherein:
The stereochemistry at the carbon atom to which the R3 and R4 groups are attached is (R);
Ar is a heteroaryl or aryl ring, preferably a pyridin-2-yl, pyridin-3-yl, quinolin-3-yl or 5-methylthiophen-2-yl ring or a phenyl ring optionally substituted with one, two or three substituent(s) selected from alkyl, heteroalkyl, alkoxy, xe2x80x94COR (where R is alkyl), xe2x80x94SO2R (where R is alkyl, amino or mono or disubstituted amino), methylenedioxy, hydroxy, halo, acylamino, amino, mono- or disubstituted amino, xe2x80x94CONRxe2x80x2Rxe2x80x3, -(alkylene)xe2x80x94CONRxe2x80x2Rxe2x80x3 (where Rxe2x80x2 and Rxe2x80x3 are hydrogen or alkyl), xe2x80x94COOR, -(alkylene)xe2x80x94COOR (where R is hydrogen or alkyl) or xe2x80x94NRSO2Rxe2x80x2 (where R is hydrogen or alkyl and Rxe2x80x2 is alkyl, amino, mono or disubstituted amino), more preferably a phenyl ring optionally substituted with one, two or three substituent(s) selected from methyl, methoxy, fluoro, chloro, dimethylamino, acetyl, hydroxy, amino, methylenedioxy, xe2x80x94SO2Me, 2-acetylaminoethyl, 2-[(R)-amino-3-methylbutyrylamino]ethyl, 2-aminoethyl, aminomethyl, hydroxymethyl, aminocarbonyl, dimethylaminocarbonyl, xe2x80x94COOH, carboxymethyl, methoxycarbonylmethyl, aminocarbonylmethyl, dimethylaminocarbonylmethyl, acetylaminomethyl, methylsulfonylamino, methylsulfonylamninomethyl, dimethylaminosulfonylaminomethyl, or dimethylamino, most preferably phenyl, 4-chlorophenyl, 3,4-difluorophenyl, 4-methylphenyl, 4-methoxyphenyl, 4-hydroxyphenyl, 4-dimethylaminophenyl, 4-aminocarbonylphenyl, 4-acetylphenyl, 4-acetylaminophenyl, 3,4-methylenedioxyphenyl, 4-methylsulfonylphenyl, 4-[(2-acetylamino)ethyl]phenyl, 4-{2-[(R)-amino-3-methylbutyrylamino]ethyl}phenyl, 4-(2-arninoethyl)phenyl, 4-(aminomethyl)phenyl, 4-(hydroxymethyl)phenyl, 2,5-dimethoxyphenyl, 3,5-dimethoxy-phenyl, 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 4-aminocarbonyl-methylphenyl, 4-acetylaminomethyphenyl, 4-methylsulfonyl-aminophenyl, 4-methylsulfonylamino-methylphenyl or 4-aminophenyl; and
Ar1 is a heteroaryl or aryl ring, preferably 1-acetylindol-3-yl, 3-methylbenzo-thiophen-2-yl, 5-nitrothiophen-3-yl or a phenyl ring optionally substituted with one, two or three substituent(s) selected from alkyl, heteroalkyl, alkoxy, halo, trifluoromethyl, nitro, or mono- or disubstituted amino, more preferably a phenyl ring substituted with one or two substituents selected from methyl, methoxy, chloro, fluoro, trifluoromethyl or nitro, most preferably 4-nitrophenyl, 4-trifluoromethylphenyl, 4-chlorophenyl, 3,4-difluorophenyl, 2,3-dichlorophenyl, 3-methyl-4-nitrophenyl, 3-chloro-4-fluorophenyl or 3,4-dichlorophenyl.
(B) Another more preferred group of compounds within group (I) is that wherein:
E is xe2x80x94NHC(O)NHxe2x80x94; and
R4 is alkyl or heteroalkyl, preferably 1-methylethyl, 1,1-dimethylethyl, 2-methylpropyl, 3-hydroxypropyl, 1-hydroxyethyl or 2-hydroxyethyl, more preferably 1-methylethyl or 1,1-dimethylethyl.
Within the preferred and more preferred groups, an even more preferred group of compounds is that wherein:
The stereochemistry at the carbon atom to which the R3 and R4 groups are attached is (R);
Ar is a heteroaryl or aryl ring, preferably a pyridin-2-yl, pyridin-3-yl, quinolin-3-yl or 5-methylthiophen-2-yl ring or a phenyl ring optionally substituted with one, two or three substituent(s) selected from alkyl, heteroalkyl, alkoxy, xe2x80x94COR (where R is alkyl), xe2x80x94SO2R (where R is alkyl, amino or mono or disubstituted arnino), methylenedioxy, hydroxy, halo, acylarino, amino, mono- or disubstituted amino, xe2x80x94CONRxe2x80x2Rxe2x80x3, -(alkylene)xe2x80x94CONRxe2x80x2Rxe2x80x3 (where Rxe2x80x2 and Rxe2x80x3 are hydrogen or alkyl), xe2x80x94COOR, -(alkylene)xe2x80x94COOR (where R is hydrogen or alkyl) or xe2x80x94NRSO2Rxe2x80x2 (where R is hydrogen or alkyl and Rxe2x80x2 is alkyl, amino, mono or disubstituted amino), more preferably a phenyl ring optionally substituted with one, two or three substituent(s) selected from methyl, methoxy, fluoro, chloro, dimethylamino, acetyl, acetylamino, hydroxy, amino, methylenedioxy, xe2x80x94SO2Me, 2-acetylaminoethyl, 2-[(R)-amino-3-methylbutyrylaminolethyl, 2-aminoethyl, aminomethyl, hydroxymethyl, aminocarbonyl, dimethylarninocarbonyl, xe2x80x94COOH, carboxymethyl, methoxycarbonylmethyl, aminocarbonylmethyl, dimethylaminocarbonylmethyl, acetylarninomethyl, methylsulfonylamino, methylsulfonylaminomethyl, dimethylaminosulfonylaminomethyl, or dimethylamino, most preferably phenyl, 3-methoxyphenyl, 3-methylsulfonylphenyl, 3-dimethylarninophenyl, 3-acetylaminophenyl, 3-acetylphenyl, 3-[(2-acetylamino)ethyl]-phenyl, 3-aminocarbonylphenyl, 3-carboxyphenyl, 2,5-dimethoxyphenyl, 3,5-dimethoxyphenyl, 3,4-dimethoxyphenyl, 3,4,5-trimethoxyphenyl, 3-aminocarbonylmethylphenyl, 3-dimethylaminocarbonylphenyl, 3-acetylaminomethyphenyl, 3-carboxymethylphenyl, 3-methylsulfonylaminophenyl, 3-methylsulfonylaminomethylphenyl or 3-aminophenyl; and
Ar1 is a heteroaryl or aryl ring, preferably 1-acetylindol-3-yl, 3-methylbenzo-thiophen-2-yl, 5-nitrothiophen-3-yl or a phenyl ring optionally substituted with one, two or three substituent(s) selected from alkyl, heteroalkyl, alkoxy, halo, trifluoromethyl, nitro, or mono- or disubstituted amino, more preferably a phenyl ring substituted with one or two substituents selected from methyl, methoxy, chloro, fluoro, trifluoromethyl or nitro, most preferably 4-nitrophenyl, 4-trifluoromethylphenyl, 4-chlorophenyl, 3,4-difluoro-phenyl, 2,3-dichlorophenyl, 3-methyl-4-nitrophenyl, 3-chloroAfluorophenyl or 3,4-dichlorophenyl.
(II) Another preferred group of compounds is that wherein:
R4 is alkyl or heteroalkyl, preferably 1-methylethyl, 1,1-dimethylethyl, 2-methylpropyl, 3-hydroxypropyl, 1-hydroxyethyl or 2-hydroxyethyl, more preferably 1-methylethyl or 1,1-dimethylethyl.
(III) Yet another preferred group of compounds is that wherein:
E is xe2x80x94C(O)N(R6)xe2x80x94 or xe2x80x94N(R7)C(O)N(R6)xe2x80x94, preferably xe2x80x94C(O)NHxe2x80x94 or xe2x80x94NHC(O)NHxe2x80x94.
The compounds of the present invention can be prepared in a number of ways known to one skilled in the art. Preferred methods include, but are not limited to, the general synthetic procedures described below.
The starting materials and reagents used in preparing these compounds are either available from commercial suppliers such as Aldrich Chemical Co., (Milwaukee, Wis., USA), Bachem (Torrance, Calif., USA), Emka-Chemie, or Sigma (St. Louis, Mo., USA) or are prepared by methods known to those skilled in the art following procedures set forth in references such as Fieser and Fieser""s Reagentsfor Organic Synthesis, Volumes 1-15 (John Wiley and Sons, 1991); Rodd""s Chemistry of Carbon Compounds, Volumes 1-5 and Supplementals (Elsevier Science Publishers, 1989), Organic Reactions, Volumes 140 (John Wiley and Sons, 1991), March""s Advanced Organic Chemistry, (John Wiley and Sons, 1992), and Larock""s Comprehensive Organic Transformations (VCH Publishers Inc., 1989). These schemes are merely illustrative of some methods by which the compounds of this invention can be synthesized, and various modifications to these schemes can be made and will be suggested to one skilled in the art having referred to this disclosure.
The starting materials and the intermediates of the reaction may be isolated and purified if desired using conventional techniques, including but not limited to filtration, distillation, crystallization, chromatography, and the like. Such materials may be characterized using conventional means, including physical constants and spectral data.
In general, compounds of Formula (I) where m, R, R1, R2, R3, R4, R5, Q, Ar and Ar1 are as defined in the Summary of the Invention are prepared by converting aminoalkyl derivatives of Formulae II(a-b) and carboxyalkyl derivatives of Formulae II(c-d) to a compound of Formula (Ia) which is then converted to the quartemary salt of Formula (I) as shown in FIG. 1 below. 
Synthesis of compounds of Formulae II (a-d) and their conversion to compounds of Formulae (Ia) and (I) are described in detail in Schemes A-J below. Synthesis of compounds of Formula (Ia) is also described in copending U.S. patent application Ser. No. 09/134,013, filed Aug. 14, 1998 whose disclosure is hereby incorporated by reference.
A compound of Formula (IIa) where T is nitrogen, m is at least 1 and R, R1, R2, R3, R4, R6, Q and Ar1 are as defined in the Summnary of the invention is prepared as illustrated in Scheme A below. 
In general, compounds of Formula (IIa) are prepared in two steps by first converting a compound of formula 1 to an N-protected aminoalkyl derivative of formula 2, followed by removal of the arnino protecting group in 2, as described in detail below.
An N-protected arinoalkyl derivative of formula 2 [where PG is an amino protecting group (e.g., tert-butoxycarbonyl (BOC), benzyloxycarbonyl (CBZ), benzyl, and the like) and R6 is hydrogen] is prepared by reacting a compound of formula 1 with a compound of formula 3
PGxe2x80x94N(R6)CR3R4(CHR)mxe2x88x921Xxe2x80x83xe2x80x83(3)
where X is an aldehyde, ketone (X=xe2x80x94C(O)R where R is alkyl), carboxy or a reactive carboxy derivative e.g., acid halide. The reaction conditions employed for the preparation of 2 depend on the nature of the X group. If X is an aldehyde or a ketone group, the reaction is carried out under reductive amination reaction conditions i.e., in the presence of a suitable reducing agent (e.g., sodium cyanoborohydride, sodium triacetoxyborohydride, and the like) and an organic acid (e.g., glacial acetic acid, trifluoroacetic acid, and the like) at ambient temperature. Suitable solvents for the reaction are halogenated hydrocarbons (e.g., 1,2-dichloroethane, chloroform, and the like). If X is a carboxy group, the reaction is carried out in the presence of a suitable coupling agent (e.g., N,N-dicyclohexylcarbodiimnide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, and the like) in a suitable organic solvent (e.g., methylene chloride, tetrahydrofuran, and the like) to give an amide intermediate. Reduction of the amide intermediate with a suitable reducing agent (e.g., diborane, lithium aluminum hydride, and the like) in an ethereal organic solvent such as ether or tetrahydrofuran then provides a compound of formula 2. If X is an acid derivative such as an acid chloride, the reaction is carried out in the presence of a suitable base such as triethylamine, pyridine in an organic solvent (e.g., methylene chloride, dichloroethane, N,N-dimethylformamide, and the like) to give an amide intermediate which is reduced to compound 2 as described above.
In general, compounds of formula 3 are commercially available or they can be prepared by methods well known in the field of organic chemistry. Some examples of such procedures are illustrated and described in detail below. 
(i) An aldehyde of formula 3 (X is a xe2x80x94CHO, and mxe2x88x921=0) is conveniently prepared from the corresponding natural or unnatural xcex1-amino acid of formula 3 where X is a carboxy group and mxe2x88x921=0 by first converting the xcex1-amino acid to the corresponding ester followed by reduction of the ester group to an aldehyde group with a suitable reducing agent such as DIBAL-H(copyright). An aldehyde of formula 3 where mxe2x88x921=1 or 2 can be prepared, if desired, from an aldehyde or ketone (X=xe2x80x94COR where R is alkyl) of formula 3 where mxe2x88x921=0 under Wittig reaction conditions. For example, an aldehyde 3 where mxe2x88x921=1 and R is hydrogen or alkyl is prepared by condensing the corresponding aldehyde or ketone of formula 3 where mxe2x88x921=0 with a Wittig reagent derived from chloromethyl methyl ether, followed by acidic hydrolysis of the resulting enol ether intermnediate. An aldehyde 3 where mxe2x88x921=2 and R are hydrogen or alkyl can be prepared by condensing the corresponding aldehyde or ketone 3 where mxe2x88x921=0 with a Wittig reagent derived from bromoacetate or 2-bromopropionate respectively, followed by sequential reduction of the double bond and the ester group in the resulting xcex1,xcex2-unsaturated ester. The ketone of formula 3 where mxe2x88x921=0 can be prepared from the xcex1-amino acids of formula 3 by converting the xcex1-amino acids 3 to a Weinreb amide, followed by treatment with a Grignard reagent of formula RMgBr where R is an alkyl group. Alternatively, the aldehyde can be prepared by oxidation of the hydroxy group in an xcex1-amino alcohol such as 2-amnino-1-propanol, and the like.
Generally, both natural and unnatural amino acids and their corresponding esters are commercially available from vendors such as Aldrich and Bachem. Examples of unnatural amino acids include, homoserine, homocysteine, N-xcex1-methylarginine, norleucine, N-methylisoleucine, phenylglycine, hydroxyproline, pyroglutamine, ornithine, 2-aminoisobutyric acid, 2-aminobutyric acid, xcex2-cyclohexylalanine, 3-(1-naphthyl)alanine, 3-(2-naphthyl)alanine, citrulline, pipecolinic acid, piperazic acid, 4-chlorophenylalanine, 4-fluorophenylalanine, sarcosine, serine ethyl ester, and alanine methyl ester are commercially available.
(ii) Compounds of formula 3 where X is a carboxy group and mxe2x88x921 greater than 0 can be prepared from the corresponding aldehyde of formula 3 (X is xe2x80x94CHO), prepared as described in (i) above, by oxidation of the aldehyde group with a suitable oxidizing agent (e.g., potassium permanganate, and the like). Alternatively, they can be prepared from the xcex1,xcex2-unsaturated ester formed in the Wittig reaction, see (i) above, by reduction of the double bond, followed by the hydrolysis of the ester group by methods well known in the art.
(iii) Compounds of formula 3 where X is xe2x80x94C(O)R (where R is alkyl) and mxe2x88x921=0, 1 or 2 can be prepared by alkylating the corresponding aldehyde of formula 3 (X is xe2x80x94CHO) with a Grignard reagent, followed by oxidation of the resulting alcohol with a suitable oxidizing agent such as potassium permanganate, and the like. Alternatively, they can be prepared from the corresponding acid of formula 3 as described in (i) above.
(iv) Compounds of formula 3 where X is an acid derivative e.g., an acid chloride can be prepared from the corresponding acids of formula 3 (X is xe2x80x94COOH), prepared as described in (iii) above, by chlorinating the carboxy group with a suitable chlorinating agent (e.g., oxalyl chloride, thionyl chloride and the like) in a suitable organic solvent such as methylene chloride and the like.
Alternatively, a compound of formula 2 can also be prepared by reacting a compound of formula 1 with an alkylating agent of formula 4
PGxe2x80x94N(R6)CR3R4(CHR)mYxe2x80x83xe2x80x834
where Y is a leaving group under alkylating conditions such as halo (e.g., chloro, bromo or iodo) or sulfonyloxy group (e.g., methylsulfonyloxy or 4-methylphenylsulfonyloxy or trifluoromethylsulfonyloxy). The reaction is carried out in the presence of a base such as sodium carbonate, sodium hydride, triethylarnine and the like. Suitable solvents are aprotic organic solvents such as tetrahydrofuran, N,N-dimethylfoimamide, and the like.
In general, compounds of formula 4 where Y is a halo or a sulfonyloxy group can be prepared from compounds of formula 3 by reducing an aldehyde, ketone or carboxy group to an alcohol, followed by treatment with a suitable halogenating agent (e.g., thionyl chloride, thionyl bromide, carbon tetrabromide in the presence of triphenylphosphine, and the like) or sulfonylating agent (e.g., methylsulfonyl chloride, para-toluenesulfonyl chloride and triflic anhydride) respectively. Suitable aldehyde, ketone and carboxy group reducing agents include lithium aluminum hydride, borane, and the like.
In some instances, a compound of Formula (IIa) can be prepared by reacting a compound of formula 1 with a conjugated nitro-olefin under Michael addition reaction conditions, followed by reduction of the nitro group under standard hydrogenation reaction conditions. Conjugated nitro-olefins are commercially available or can be prepared by known literature procedures e.g., see Corey, E. J. et al., J. Am. Chem. Soc, 100(19), 8294-5, (1978).
The N-protected aminoalkyl derivative 2 is converted to a compound of Formula (IIa) by removal of the amino protecting group. The conditions utilized depend on the nature of the protecting group. For example, if the protecting group is the tert-butoxycarbonyl group it is removed under acidic hydrolysis reaction condition whereas if it is the benzyl group it is removed under catalytic hydrogenation reaction conditions.
A compound of Formula (IIa) where R6 is other than hydrogen can be prepared, if desired, by alkylating the corresponding compound of Formula (IIa) where R6 is hydrogen with an alkylating agent R6Y where Y is a leaving group under alkylating conditions, utilizing the reaction conditions described above.
Compounds of formula 1 can be prepared from suitably N-protected piperidinones by known procedures. Some examples of such procedures are described below:
(i) Compounds of formula 1 where Q is xe2x80x94C(O)xe2x80x94 or an alkylene chain are prepared by reacting a suitably N-protected4piperidinone with a Wittig reagent Brxe2x88x92(Ph)3P+-alkylene-Ar1 to give an alkylidene intermediate. Treatment of the alkylidene intermediate with borane, followed by oxidation of the resulting alkylborane with an oxidizing agent such as chromic acid under the reaction conditions described in Brown, Garg J. Am. Chem. Soc. 83, 2951 (1961) and removal of the N-protecting group provides a compound of formula 1 where Q is xe2x80x94COxe2x80x94. Reduction of the olefinic bond in the alkylidene intermediate followed by removal of the N-protecting group provides compounds of formula 1 where Q is an alkylene chain. A detailed description of the synthesis of a piperidine of formula 1 by this method where Q is an alkylene chain is given in Example 1.
(ii) Compounds of formula 1 where Q is xe2x80x94O-alkylene-Ar1 can be prepared by reacting a 4-hydroxypiperidine with an alkylating agent of formula Ar1xe2x80x94Qxe2x80x94Y where Y is a leaving group under alkylating reaction conditions as defined previously.
(iii) Compounds of formula 1 where Q is xe2x80x94NHxe2x80x94alkylene-Ar1 can be prepared by reacting an N-protected-4-piperidone with an amine of formula NH2-alkylene-Ar1 under reductive amination reaction conditions as described previously.
4-hydroxypiperidine and 4-piperidinone are commercially available.
A compound of Formula (IIb) where U is nitrogen, m is 1 and R, R1, R2, R3, R4, R6, Q and Ar1 are as defined in the Summary of the invention can be prepared from a compound of formula 5 as illustrated in Scheme B below. 
A compound of Formula (IIb) where m is 1 can be prepared, as shown in method (a), by reacting a compound of formula 5 with a phosphonate ylide of formula 6 under Wittig reaction conditions, i.e., in the presence of a strong non-nucleophilic base (e.g., sodium hydride, sodium amide, and the like) and in a suitable aprotic organic solvent (e.g., tetrahydrofuran and the like) to give an xcex1,xcex2-unsaturated ester of formula 7. The xcex1,xcex2-unsaturated ester 7 is converted to the corresponding alcohol derivative 8a (m=1) by first converting 7 to an aldehyde, followed by 10 treatment with an organometallic reagent such as a Grignard reagent or an organolithium reagent of formula R4MgBr or R4Li, respectively. The double bond is reduced under hydrogenation reaction conditions and the ester group is reduced to the aldehyde group with a suitable reducing agent such as DIBAL-H(copyright). The alcohol 8a is then converted to a compound of Formula (IIb) by oxidation of the alcohol group to the ketone group, followed by treatment with an amine of formula NH(R6) under reductive arnination reaction conditions. The oxidation reaction is carried in with a suitable oxidizing reagents such as pyridinium dichromate in an aprotic solvent such as dimethylformamide and the like.
A compound of Formula (IIb) where m is 0 can be prepared, as shown in method (b) from a compound of formula 9, by converting 9 to the corresponding alcohol derivative 8b (m=0) by reduction of the ester group to the aldehyde followed by treatment with a suitable organometallic reagent. Compound 8b is then converted to a compound of Formula (IIb) where m is 0 by carrying out the oxidation and reductive anination steps, utilizing the reaction conditions described above. Compounds of Formula (IIb) where m is 0 can also be prepared by the procedures described in PCT application Publication No. WO 92/12128.
Compounds of formula 5 or 9 can be prepared by N-alkylating a 4-piperidone or ethyl isonipecotate with a compound of formula Ar1xe2x80x94Qxe2x80x94Y where Y is a leaving group under alkylating conditions as described in Scheme A above.
A carboxyalkyl derivative of Formula (IIc) where T is nitrogen, m, R1, R2, R3, R4, Q and Ar1 are as defined in the Summary of the invention can be prepared from a compound of formula 1 as illustrated in Scheme C below. 
A carboxy derivative of Formula (IIc) is prepared, as shown above, by reacting a compound of formula 1 with an alkylating agent of formula 10 where Y is halo or sulfonyloxy group, followed by hydrolysis of the ester group. The alkylation reaction is carried under the reaction conditions described previously ((see scheme A). The hydrolysis of the ester group is carried out in the presence of an aqueous base (e.g., sodium hydroxide, lithium hydroxide, and the like) in an alcoholic organic solvent such as methanol, ethanol, and the like. The reaction proceeds either at ambient temperature or upon heating. Alternatively, a carboxyethyl derivative of Formula (IIc) where R3 is hydrogen is prepared by reacting a compound of formula 1 with an oc,-unsaturated ester of formula 11 under Michael addition reaction conditions i.e., in the presence of a suitable base such as methoxide and in a protic organic solvent (e.g., methanol, ethanol and the like) to give a 3-propionate derivative of formula 12. Hydrolysis of the ester group in 12 then provides the corresponding carboxyethyl derivative of Formula (IIc) where R3 is hydrogen.
Compounds of formula 1 are prepared as described previously in Schemes A. Compounds of formula 10 and 11 are either commercially available or can be prepared by methods known in the art. For example, halo acids and xcex1,xcex2-unsaturated ester such as methyl 2-bromo-2-methylpropionate, methyl 2-bromopropionate, methyl 3-bromo-2-methylpropionate, methyl xcex1-bromophenylacetate, methyl methacrylate are commercially available.
A carboxyalkyl derivative of Formula (IId) where U is nitrogen, m, R1, R2, R3, R4, Q and Ar1 are as defined in the Summary of the invention can be prepared from a compound of formula 5 or 13 respectively, as illustrated in Scheme D below. 
A carboxyalkyl derivative of Formula (IId) where can be prepared by reacting a compound of formula 5 or 13 with a Wittig reagent of formula Br(Ph3P)(CHR)mCR3R4CO2Et (m=1), followed by reduction of the double bond and hydrolysis of the ester group to the acid in the resulting unsaturated ester 14a or 14b , as described previously.
Compounds of Formula (Ia) where E is xe2x80x94C(O)N(R6)xe2x80x94 are prepared as described in Scheme E below: 
A compound of Formula (Ia) where E is an amide group can be prepared, either:
(i) by reacting a compound of Formula II(a-b) with an acylating reagent Arxe2x80x94Fxe2x80x94C(O)L, where L is a leaving group under acylating conditions, such as a halo (particularly Cl or Br) or imidazolide. Suitable solvents for the reaction include aprotic polar solvents (e.g., dichloromethane, THF, dioxane and the like). When an acyl halide is used as the acylating agent the reaction is carried out in the presence of a non-nucleophilic organic base (e.g., triethylamine or pyridine, preferably pyridine); or
(ii) by heating a compound of Formula II(a-b) with an acid anhydride. Suitable solvents for the reaction are tetrahydrofuran, dioxane and the like.
Compounds of Formula (Ia) where E is xe2x80x94N(R7)C(O)N(R)xe2x80x94 or xe2x80x94N(R7)C(S)N(R6)xe2x80x94 are prepared as described in Scheme F below: 
A compound of Formula (Ia) where E is a urea/thiourea group can be prepared, either:
(i) by reacting a compound of Formula II (a-b) with an activating agent such as carbonyl diimidazole/thiocarbonyl diimidazole, followed by nucleophilic displacement of the imidazole group with a primary or secondary amine. The reaction occurs at ambient temperature. Suitable solvents include polar organic solvents (e.g., tetrahydrofuran, dioxane and the like);
(ii) by reacting a compound of Fonnula II (a-b) with a carbamoyllthiocarbamoyl halide. The reaction is carried out in the presence of a non-nucleophilic organic base. Suitable solvents for the reaction are dichloromethane, 1,2-dichloroethane, tetrahydrofuran or pyridine; or
(iii) by reacting a compound of Formula II (a-b) with an isocyanate/isothiocyanate in an aprotic organic solvent (e.g., benzene, tetrahydrofuran, dimethylformamide and the like).
A detailed description of the conversion of a compound of Formula (IIa) to a compound of Formula (Ia) where E is xe2x80x94NHC(O)NHxe2x80x94 is given in Example 1.
Compounds of Formula (Ia) where E is xe2x80x94SO2N(R6)xe2x80x94 are prepared as described in Scheme G below: 
A compound of Formula (Ia) where E is a sulfonamido group can be prepared by reacting a compound of Formula II(a-b) with a sulfony] halide, utilizing the reaction conditions described in method (i) of Scheme E. Sulfonyl halides are commercially available or may be prepared by methods such as those described in (1) Langer, R. F.; Can. J. Chem. 61, 1583-1592, (1983); (2) Aveta, R.; et. al.; Gazetta Chimica Italiana, 116, 649-652, (1986); (3) King, J. F. and Hillhouse, J. H.; Can. J. Chem.; 54, 498, (1976); and (4) Szymonifka, M. J. and Heck, J. V.; Tet. Lett.; 30, 2869-2872, (1989).
Compounds of Formula (Ia) where E is xe2x80x94N(R7)SO2N(R6)xe2x80x94 are prepared as described in Scheme H below: 
A compound of Formula (Ia) where E is a sulfamide group can be prepared by reacting a compound of Formula It (a-b) with a sulfamoyl halide, utilizing the reaction conditions described in method (i) of Scheme E. Sulfamoyl halides are commercially available or may be prepared by methods such as those described in Graf, R; German Patent, 931225 (1952) and Catt, J. D. and Matler, W. L; J. Org. Chem., 39, 566-568, (1974).
Compounds of Formula (Ia) where E is xe2x80x94N(R7)C(O)xe2x80x94 are prepared as described in Scheme I below: 
A compound of Formula (Ia) where E is an inverse amide can be prepared by reacting a compound of Formula II(c-d) with an amine in the presence of a suitable coupling agent (e.g., N,N-dicyclohexylcarbodiimide, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide, and the like) in a suitable organic solvent such as methylene chloride, tetrahydrofuran, dimethylformamide and the like.
A compound of Formula (I) where T or U is xe2x80x94N+R5xe2x80x94 can be prepared from a compound of Formula (Ia) as shown in Scheme J below. 
A compound of Formula (Ia) is converted to a compound of Formula (I) where T or U is xe2x80x94N+R5xe2x80x94 by reacting it with an alkylating agent of formula R5X where R5 is as defined in the Summary of the Invention and X is a leaving group such as halo (bromide or iodide, preferably iodide), tosylate, mesylate, and the like. Alkylating agents such as methyl iodide, ethyl iodide, ethyl toluenesulfonate, 2-hydroxyethyl iodide and the like are commercially available.
A compound of Formula (I) where Xxe2x88x92 is iodide can be converted to a corresponding compound of Formula (I) where X is chloride by utilizing a suitable ion exchange resin such as Dowex 1x8-50.
Detailed descriptions of the conversion of a compound of Formula (Ia) to a compound of Formula (I) where E is xe2x80x94NHC(O)NHxe2x80x94 is given in Examples 1-3.
The compounds of the invention are CCR-3 receptor antagonists and therefore should inhibit recruitment of eosinophil, T cells, basofils and mast cells by chemokines such as RANTES, eotaxin and MCP-3. The quaternary salts of the present invention are, in general, more potent than their corresponding non-quaternized piperidine analogs. Therefore, compounds of this invention and compositions containing them are useful in the treatment of eosiniphil-induced diseases such as asthma, rhinitis, eczema, and parasitic infections in mammals, especially humans.
The CCR-3 antagonistic activity of the compounds of this invention may be measured by in vitro assays such as ligand binding and chemotaxis assays as described in more detail in Examples 5, 6 and 7. It can be assayed in vivo by Ovalbumin induced Asthma in Balb/c Mice Model as described in more detail in Example 8.
In general, the compounds of this invention will be administered in a therapeutically effective amount by any of the accepted modes of administration for agents that serve similar utilities. The actual amount of the compound of this invention, i.e., the active ingredient, will depend upon numerous factors such as the severity of the disease to be treated, the age and relative health of the subject, the potency of the compound used, the route and form of administration, and other factors.
Therapeutically effective amounts of compounds of Formula (I) may range from approximately 0.005-20 mg per kilogram body weight of the recipient per day; preferably about 0.01-10 mg/kg/day. Thus, for administration to a 70 kg person, the dosage range would most preferably be about 0.7 mg to 0.7 g per day.
In general, compounds of this invention will be administered as pharmaceutical compositions by any one of the following routes: oral, systemic (e.g., transdermal, intranasal or by suppository), or parenteral (e.g., intramuscular, intravenous or subcutaneous) administration. The preferred manner of administration is oral using a convenient daily dosage regimen which can be adjusted according to the degree of affliction. Compositions can take the form of tablets, pills, capsules, semisolids, powders, sustained release formulations, solutions, suspensions, elixirs, aerosols, or any other appropriate compositions.
The choice of formulation depends on various factors such as the mode of drug administration (e.g., for oral administration, formulations in the form of tablets, pills or capsules are preferred) and the bioavailability of the drug substance.
For liposomal formulations of the drug for parenteral or oral delivery the drug and the lipids are dissolved in a suitable organic solvent e.g. tert-butanol, cyclohexane (1% ethanol). The solution is lypholized and the lipid mixture is suspended in an aqueous buffer an allowed to form a liposome. If necessary, the liposome size can be reduced by sonification. (see., Frank Szoka, Jr. and Demetrios Papahadjopoulos, xe2x80x9cComparative Properties and Methods of Preparation of Lipid Vesicles (Liposomes)xe2x80x9d, Ann. Rev. Biophys. Bioeng., 9:467-508 (1980), and D. D. Lasic, xe2x80x9cNovel Applications of Liposomesxe2x80x9d, Trends in Biotech., 16:467-608, (1998))
Recently, pharmaceutical formulations have been developed especially for drugs that show poor bioavailability based upon the principle that bioavailability can be increased by increasing the surface area i.e., decreasing particle size. For example, U.S. Pat. No. 4,107,288 describes a pharmaceutical formulation having particles in the size range from 10 to 1,000 nm in which the active material is supported on a crosslinked matrix of macromolecules. U.S. Pat. No. 5,145,684 describes the production of a pharmaceutical formulation in which the drug substance is pulverized to nanoparticles (average particle size of 400 nm) in the presence of a surface modifier and then dispersed in a liquid medium to give a pharmaceutical formulation that exhibits remarkably high bioavailability.
The compositions are comprised of in general, a compound of Formula (I) in combination with at least one pharmaceutically acceptable excipient. Acceptable excipients are non-toxic, aid administration, and do not adversely affect the therapeutic benefit of the compound of Formula (I). Such excipient may be any solid, liquid, semi-solid or, in the case of an aerosol composition, gaseous excipient that is generally available to one of skill in the art .
Solid pharmaceutical excipients include starch, cellulose, talc, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, magnesium stearate, sodium stearate, glycerol monostearate, sodium chloride, dried skim milk and the like. Liquid and semisolid excipients may be selected from glycerol, propylene glycol, water, ethanol and various oils, including those of petroleum, animal, vegetable or synthetic origin, e.g., peanut oil, soybean oil, mineral oil, sesame oil, etc. Preferred liquid carriers, particularly for injectable solutions, include water, saline, aqueous dextrose, and glycols.
Compressed gases may be used to disperse a compound of this invention in aerosol form. Inert gases suitable for this purpose are nitrogen, carbon dioxide, etc.
Other suitable pharmaceutical excipients and their formulations are described in Remington""s Pharmaceutical Sciences, edited by E. W. Martin (Mack Publishing Company, 18th ed., 1990).
The level of the compound in a formulation can vary within the full range employed by those skilled in the art. Typically, the formulation will contain, on a weight percent (wt %) basis, from about 0.01-99.99 wt % of a compound of Formula (I) based on the total formulation, with the balance being one or more suitable pharmaceutical excipients. Preferably, the compound is present at a level of about 1-80 wt %. Representative pharmaceutical formulations containing a compound of Formula (I) are described in Example 4.